Peripheral pain management

ABSTRACT

A system including a processor configured to be coupled to an electrical lead that is configured to sense electrical activity in a patient, a memory coupled to the processor, the memory containing computer readable instructions that, when executed by the processor, cause the processor to detect a pain signature in the sensed electrical activity, determine a treatment protocol in response to the detected pain signature, and cause the treatment protocol to be delivered to the patient via the electrical lead.

RELATED APPLICATIONS

This application is a national stage application, filed under 35 U.S.C.§371, of International Application No. PCT/US2011/034203 filed Apr. 27,2011, which claims the benefit of U.S. Provisional Application No.61/328,583, filed Apr. 27, 2010, the contents of which are incorporatedby reference in their entireties.

BACKGROUND

More than 11 million Americans report chronic pain as a significantdisability. The financial burden of chronic pain in the United Statesalone is estimated at higher than $100 billion a year, including lostproductivity and medical expenses. Viewed globally, there is a largeunderserved population for pain management medications and/or therapies.

Chronic pain is typically classified as pain lasting more than 6 monthsand generally divided into three main types: nociceptive, psychogenic orneuropathic (e.g., due to nerve injury) although the distinction betweenthese types can be blurred. Especially true for chronic neuropathicpain, current treatment options including opioids and nonsteroidalanti-inflammatory drugs (e.g. COX inhibitors) are often ineffective,contraindicated or associated with significant gastrointestinal andcardiac side effects, sedation, respiratory depression, addiction anddrug abuse. It is widely believed that pharmacotherapy, surgicalablation, and externally applied non-drug therapies (e.g. transcutaneouselectrical nerve stimulation and acupuncture) have all reached a ceilingwell below the desired level of patients and clinicians. Novel ideas arethus needed in pain research.

SUMMARY

The invention provides a solution to the long-standing problem ofaccurate identification of clinical pain and reliable therapeuticintervention to alleviate such pain. Chronic clinical pain includesneuropathic pain such as that associated with direct nerve damage,amputation, chemotherapy, diabetes, HIV infection or AIDS, MultipleSclerosis, shingles, sciatic nerve compression or injury, as well asspine surgery.

Accordingly, a method of identifying a subject characterized assuffering from chronic pain, e.g., chronic neuropathic pain, is carriedout by detecting a pain signature comprising an pattern of neuronalfiring compared to a normal pattern of neuronal firing, e.g., a patternobtained from a subject or a cohort of subjects that have beencharacterized as not suffering from pain. The pattern of firing isobtained from a single neuron or a plurality of neurons. The brain of asubject afflicted with chronic pain has stored a pain signature. Thepattern comprises an elevated evoked response to stimuli, rhythmicafter-discharge signaling, and/or increased spontaneous backgroundfiring. The pain and neuronal firing pattern subsists after an injuryheals or is completely unrelated to a stimulus, e.g., an injury, or thedegree of a stimulus. In one example, the pain signature comprises apattern of neuronal burst-firing, each burst of the burst firingcomprising at least 10 times, 50 times, 100 times or more, the number ofspikes compared to a control non-pain pattern. An exemplary painsignature comprises a pattern of burst-firing that is characterized byone or more of the following measurable parameters: (a) a maximuminterval signifying burst onset (6 ms); (b) a maximum interspikeinterval (9 ms); (c) longest increase in interspike interval within aburst (2 ms); (d) a minimum number of spikes within a burst (2). Anaberrant pattern or pain signature is further characterized by aspontaneous high frequency rhythmic oscillation of long epoch.

A method of preventing or reducing pain perception involves identifyinga subject using the criteria described above and administering to thesubject at least one electrical pulse to the subject, the electricalpulse being at least about 100, 150, or 200 Hz, between about 1 andabout 3 volts, between about 1 and about 3 milliampere, and betweenabout 0.25 and about 1 second in duration. Rather than stimulating theaberrantly firing neurons back to a recovery pattern, the electricalpulse of at least about 100 Hz jams or halts the pain circuitry at thelevel of the source. Subjects to be diagnosed and/or treated includehuman patients as well as animals such as companion animals (e.g., dogs,cats) as well as livestock and performance animals (e.g., horses,cattle, and the like).

The invention includes an anatomically-based andneurotechnology-oriented pain therapy system to achieve neuromodulationof specific brain regions, for example using transcutaneous magneticfields or chronically implanted electrodes. In general, in an aspect,the invention provides a system including a processor configured to becoupled to an electrical lead that is configured to sense electricalactivity in a patient, a memory coupled to the processor, the memorycontaining computer readable instructions that, when executed by theprocessor, cause the processor to detect a pain signature in the sensedelectrical activity, determine a treatment protocol in response to thedetected pain signature, and cause the treatment protocol to bedelivered to the patient via the electrical lead.

In general, in another aspect, the invention provides a system includinga processor configured to provide an electrical treatment protocol to apatient, the electrical treatment protocol being configured to treatchronic pain in the patient, the treatment protocol including providingat least one electrical pulse to the patient, the electrical pulse beingat least about 150 Hz, between about 1 and about 3 volts, between about1 and about 3 milliampere, and between about 0.25 and about 1 second induration.

In general, in a further aspect, the invention provides a method ofidentifying a subject comprising chronic pain, including detecting apain signature comprising a pattern of neuronal firing, said patterncomprising an elevated evoked response to stimuli, rhythmicafter-discharge signaling, and increased spontaneous background firing.

In general, in still another aspect, the invention provides a method ofidentifying a subject comprising chronic pain, comprising detecting apain signature comprising a pattern of burst-firing, each burst of saidburst firing comprising at least 10 times the number of spikes comparedto a control non-pain pattern.

In general, in yet another aspect, the invention provides a method ofidentifying a subject comprising chronic pain, comprising detecting apain signature including a pattern of burst-firing, wherein said patterncomprises burst-firing, said burst firing including (a) a maximuminterval signifying burst onset (6 ms), (b) a maximum interspikeinterval (9 ms), (c) longest increase in interspike interval within aburst (2 ms), or (d) a minimum number of spikes within a burst (2).

In general, in an even further aspect, the invention provides a methodof preventing or reducing pain perception, comprising identifying asubject, and administering to said subject at least one electrical pulseto the subject, the electrical pulse being at least about 150 Hz,between about 1 and about 3 volts, between about 1 and about 3milliampere, and between about 0.25 and about 1 second in duration.

Various aspects of the invention may provide one or more of thefollowing capabilities. The efficiency, battery life, and device life ofdevices used for neurostimulation can be improved over prior techniques.More physiologically relevant brain structures can be targeted comparedwith prior techniques. Side effects can be reduced compared with priortechniques. The temporal and overall amount of delivered current can bereduced compared with prior techniques. The likelihood of excessivetissue exposure, which has been thought to cause long-term changes andside effects, can be reduced compared with prior techniques. Thenecessity for combined pharmacologic intervention can be reduced, orpossibly eliminated compared prior techniques. Chronic pain can beempirically diagnosed.

These and other capabilities of the invention, along with the inventionitself, will be more fully understood after a review of the followingfigures, detailed description, and claims. Other features and advantagesof the invention will be apparent from the following description of thepreferred embodiments thereof, and from the claims. All references citedherein are incorporated by reference.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a diagram of a classic ‘pain pathway’ illustrating thespinothalamic tract (STT) and how nociceptive information is transmittedfrom the periphery via the dorsal root ganglion (DRG) to centralstructures including the ventroposterior lateral (VPL) nucleus of thethalamus to the cerebral cortex (Cc).

FIG. 2A is a diagram of a deep brain stimulation (DBS) system.

FIG. 2B is a flow diagram showing a diagnostic protocol for pain.

FIG. 3 is a graphical representation of a representative example of asingle unit recording comparison between CCI and Naive subjects. Eachgraph displays the firing (mV) of a single WDR neuron over time andcorresponding peristimulus time histograms of the data. Both VPL neuronsused for recording possessed receptive fields at the hind-paw. CCI modelrats display an increase in spontaneous background firing (shown inyellow), elevated pressure and pinch responses (green), and rhythmicafter-discharge signaling (blue).

FIG. 4 is a bar graph showing a comparison of the mean evoked responsefrequency over all group 1 (CCI) and group 2 (naive) rats. Statisticallysignificant increases in spontaneous activity and after discharge, aswell as evoked pressure and pinch responses are shown (*P<0.05).

FIG. 5 is a line graph showing a comparison of rat withdrawal latencybetween the hindpaw ipsilateral and contralateral to the sciatic nerveinjury as measured during behavioral testing. The withdrawal latency ofthe injured hindpaw (pink) is significantly lower than baseline by days6 and 7 (* P<0.0.5).

FIG. 6 is a graph showing a representative example of a comparisonbetween Isoflurane and Pentobarbital anesthesia. Activity in a singleVPL unit is recorded under conditions of Isoflurane (2%) followed byPentobarbital 20 minutes later (i.v. 40 mg/kg/hr) in a single animal. Nomajor difference in spontaneous or evoked activity is apparent.

FIG. 7 is a bar graph showing an electrophysiological response tomechanical stimuli in pre- and post-HFS conditions. VPL neurons of group5 rats post HFS are significantly less reactive to mechanical stimulivia brush, Von Frey, pressure, and pinch than during initial baselinerecording (P<0.05).

FIG. 8 is a bar graph showing a background electrophysiologicalcomparison in pre- and post-HFS conditions. VPL neurons of group 5 ratspost HFS display significantly lower levels of afterdischarge (20seconds post mechanical stimulation) while levels of background firingremain relatively constant (* P<0.05).

FIG. 9 is a line graph showing withdrawal Latency of the ipsilateralhindpaw in deep brain stimulation (DBS) group 6 rats. Within 5 minutesof neurostimulation, withdrawal latency significantly increases, witheffects lasting 0.5-2 hrs.

FIG. 10 is a bar graph showing OX-42 antibody staining comparisonbetween CCI and CCI+DBS animals in VPL contralateral to CCI (i.e.receiving pain input from the injured leg and the implant), DBS subjectsdisplayed significantly higher levels of OX-42 antibody staining ascompared with untreated CCI subjects (*P<0.05). Reflected differenceswere measured as changes in the mean grayscale value of photographedmicroscope images of the VPL, indicating a physiologic local effect forHFS.

FIG. 11 is a bar graph GFAP antibody staining comparison between CCI andCCI+DBS animals in VPL contralateral to CCI (i.e. receiving pain inputfrom the injured leg and the implant). Measured differences in GFAPstaining were not statistically significant, suggesting lack ofastrogliosis, tissue scarring or prominent neuroinflammatory reaction toHFS.

FIG. 12 is a series of bar graph showing burst characterization inresponse to various stimuli, e.g., brush, Von Frey, pressure, and pinch.

FIG. 13 is a graphical representation showing neuronal activity from asingle unit in the thalamus (VPL) with receptive field in the injuredhindpaw one week after CCI. Note distinct firing pattern associated withCCI and emergence of spontaneous high frequency rhythmic oscillation oflong epoch (˜) after pinch. The high spontaneous rate of firing is onlybriefly interrupted by application of lidocaine (4%) directly on thedorsal surface of the spinal cord at upper thoracic level, whereasevoked responses to brush and pinch disappear. Note sustained and moreelevated spontaneous firing within seconds after lidocaine application,indicating a phenomenon independent of peripheral or caudal input fromthe spinal cord (i.e. inherent within the brain).

FIG. 14 is a drawing and a photograph of rodent into whichmicroelectrodes were implanted in the brain with tips located in the VPLnucleus of the thalamus. Signal generated from these electrodes (RE) wasrelayed to a data acquisition system via a head stage fixed to the skullof the animal. Neuropathic pain was measured behaviorally and induced bychronic constriction injury (CCI) of the sciatic nerve, a ‘mixed’ nervethat receives sensory input from the leg and connects with centralnervous system (CNS) circuitry projecting into the VPL. To evoke thermalnociception, a laser beam was focused on the plantar hindlimb to illicita withdrawal behavior of measurable latency.

FIG. 15 is a photograph of a modified microelectrode design. Electrodesegments were fused together with Epoxy resin in order to form arespective cathode and anode during DBS trials. The Teflon coating wascut to reveal 0.5 mm of silver wire on each electrode. Cathode and Anodeare separated by 1 mm from tip to tip as shown.

FIG. 16 is a photograph of a recording setup. Following craniotomy, themicroelectrode was lowered to a depth of 5-6 mm until an appropriate VPLunit was isolated for recording.

FIG. 17 is an illustration of the relative position of the bipolarstimulating electrodes in relation to the VPL, and the area directlyaffected by stimulation (shaded) based on several modeling studies(refer to text).

FIG. 18A is a line graph, and FIG. 18B is a bar graph. FIG. 18A showsrepresentative examples of tonic firing in two units under naïve and CCIconditions. Note increased rate of spontaneous firing and firing evokedby pressure (Pr), pinch (Pi) and afterdischarge (AD) in CCI rat comparedto naïve. FIG. 2B shows mean rate of firing in two groups of VPL neuronsin naïve and CCI rats (n=9-11/gr).

FIGS. 19A-B are line graphs, and FIG. 19C is a bar graph. FIG. 19A showsa representative example of spontaneously rhythmic oscillation (greyshade), which was abolished after complete spinal transection (arrow,asterisk indicates absence of a response to brush after transection).Rhythmic oscillation was observed in 3/9 (33%) neurons in rats with CCI.FIG. 19B shows phase histograms during rhythmic oscillation fitted witha sine wave curve (before spinal transection, left panel). Noteelimination of oscillation after transaction reflected by a much loweramplitude sine wave (right panel). FIG. 19C shows sine wave parametersin neurons with oscillation fitted to phase histograms.

FIGS. 20A-B are line graphs showing representative examples of theeffect of HFS (100 Hz) and LFS (25 Hz) on the firing rate of two VPLneurons in two rats with CCI. HFS attenuated all evoked activity andafterdischarge, whereas spontaneous firing remained unchanged. Noteincreasing effects with incremental increases in voltage, compared tolack of prominent effect using LFS. FIGS. 20C-D are graphs showing meanpercent change in firing rates after HFS (n=9 units) or LFS (n=5 units)compared to pre-stimulation baselines for each unit. HFS significantlyinhibited all evoked responses and after discharge in units recordedfrom CCI rats, except spontaneous activity, in contrast to LFS which hadno significant effect.

FIG. 21 is a graphical representation showing examples of burst firingunder naïve and CCI conditions during peripheral brush stimulation.Upper traces in each panel represent burst activity with correspondingspiking activity in lower traces (shaded insets represent expanded timescales of activity periods in grey boxes). Note increased burst eventsand number of spikes per burst after CCI.

FIG. 22 is a series graphical representations showing a detailedanalysis of burst firing showing significantly different patterns inrats with CCI compared to naïve. Evoked burst activity occurred in naïveand CCI rats (although spontaneous burst was very rare in naïve rats).Burst parameters were different in CCI rats, showing a consistentincrease in the number of bursts and % spikes for all firing modalities,whereas inter-burst periods were consistently decreased. HFS reversedthese changes to near ‘normal’ or naïve values.

FIG. 23 is a series graphical representations showing local fieldpotentials (upper traces) before, during and after HFS withcorresponding power spectra (lower panels) showing a prominent peakbetween 10-20 Hz (corresponding to β activity; arrow). HFS had no effecton this peak or the overall power distribution up to 500 Hz duringspontaneous firing (note emergence of peaks at 200 Hz matchingstimulation frequency and a harmonic thereof at 400 Hz; arrowheads).

FIG. 24A is a bar graph, and FIGS. 24B-C are line graphs. FIG. 24A showsmean withdrawal latencies before and after CCI (n=5 rats). Pre-CCIvalues represent average withdrawal latencies in both hindpaws whichwere not significantly different, whereas post-CCI latency wassignificantly decreased in ipsilateral (injured) hindpaws compared tocontralateral (uninjured) hindpaws, indicating thermal hyperalgesia.FIG. 24B shows the effect of HFS (arrows) on withdrawal latencies inipsilateral and contralateral hindpaws (arrowhead denotes shamcondition, i.e. connecting the stimulating electrodes to the stimulatorwithout applying voltage). FIG. 24C shows mean withdrawal latencies 5min before HFS and at 5 and 10 min after HFS showing significantincrease in latency 5 min after HFS (n=4 rats), suggesting attenuationof hyperalgesia.

FIG. 25 is a bar graph showing mean rate of firing in VPL neurons withreceptive fields excluding the hindpaws from two groups of naïve and CCIrats (n=9-11/gr), showing no difference in firing rates except forfiring evoked by brush.

FIG. 26A-B are graphical representations showing mean percent change infiring rates in two groups of VPL neurons under CCI and naïveconditions. FIG. 26A shows that relatively ‘moderate’ microstimulation(100 HZ, 0.5 V, 1 s duration pulse) resulted in a significantlydecreased firing evoked by pressure and pinch as well as afterdischarge(n=4 out of 9 neurons). FIG. 26B shows that HFS decreased the firingrate in naïve rats, reaching significant levels for all firingmodalities except for the weakest von Frey filament stimulation (0.6 g)and afterdischarge (n=6 units).

FIG. 27 is a graphical representation showing Mean withdrawal latenciesin hindpaws contralateral to injury in CCI rats 5 min before HFS and at5 and 10 min after HFS showing non-significant change in latency (n=4rats).

FIG. 28 is a series of photographs and a bar graph. Chronicmicroelectrode implant had no effect on the mean ratio of OX-42 or GFAPimmunofluorescence intensity in the vicinity of stimulating electrodetips, suggesting limited or absent glial activation or reactive gliosis(n=4 rats).

FIG. 29 is a series of tables (Table 1, Table 2, Table 3, Table 4).

FIG. 30 is a graph showing a representative record of firing of neuronsin the thalamus in an awake patient with chronic pain. Pain wasrepeatedly induced during continuous recording of the neural activity(from upper left to lower right). Dotted lines indicate tapping of thehand for activation of touch-evoked pain. Solid lines indicate pain wasverbally reported by the patient.

FIG. 31 is a graph of a representative record of a unit in the thalamusof a rat with spinal cord injury pain to illustrate burst events(compare with FIG. 30). During 60 sec of firing activity, 2 burst epochsalternated with unique periods identified as ‘a’ and ‘b’. These 2 epochsspontaneously alternated in a repeated manner separated by interepochintervals of low firing activity, exhibiting a rhythmic oscillatoryfiring pattern.

FIG. 32 is a line graph showing a spectral analysis of spontaneousactivity. Mean power spectra for patients with Complex Regional PainSyndrome (CRPS) (red) and normal subjects (black) showing shifting ofbrain activity to a lower frequency in pain patients.

FIG. 33 is a graphical representation of local field potential (LFP)recorded from the VPL contralateral to CCI; Spontaneous activity isfollowed by increased activity evoked by brushing of the receptive filedin the injured paw (t=19-40 s).

FIG. 34 is a series of graphs showing spontaneous activity and activityin response to brushing of the contralateral paw. Spectral power wascomputed using FFT analysis of the recorded signal from the VPLbilaterally and normalized for each VPL. A broad peak (1-15 Hz) wasobserved under spontaneous conditions in CT, which more prominentlyshifted leftwards (1-3 Hz) in CCI. During evoked responses, the peak ataround 5 Hz was more prominent in CCI compared to CT, with a broaderpower distribution in the higher-frequency (5-15 Hz) region. Overallpower was increased bilaterally during evoked responses to brush;however, this increase was almost 3 folds higher in CCI (note increasedevoked/spontaneous ratio of area power from 1.16 in CT to 3.05 in CCI).Red plots represent Gaussian data fit.

FIG. 35 is a series of illustrations depicting LFP recordings of the sixgroups (Gr, n=8/Gr, total 48 rats; Exp: Experimental, Ct: Control):

-   -   Gr1: Record LFP in somatosensory cortex (SI) first ipsilateral        (Ct) then contralateral (Exp) to CCI before/after SCS.    -   Gr2: Record LFP in SI first contralateral (Exp) then ipsilateral        (Ct) to CCI before/after SCS.    -   Gr3: Record LFP in VPL first ipsilateral (Ct) then contralateral        (Exp) to CCI before/after SCS.    -   Gr4: Record LFP in VPL first contralateral (Exp) then        ipsilateral (Ct) to CCI before/after SCS.    -   Gr5: Record LFP in SI in naïve before/after SCS.    -   Gr6: Record LFP in VPL in naïve before/after SCS.

DETAILED DESCRIPTION

Chronic pain is a serious challenge in terms of pathophysiology,diagnosis, therapy and social burden. Studies in humans and laboratoryanimals suggest a relationship between intractable pain and ectopicneuronal activity in thalamic and cortical areas, leading todysfunctional connectivity in the brain's ‘pain network’. Contributingto this network are dense interconnections between thalamic and corticalmodules whose interactions are being investigated in terms ofdirectionality and temporal dynamics. In humans, intracranial electroderecordings demonstrate altered neuronal activity within these networksin patients with chronic pain. Single-cell electrophysiology andmagneto-encephalographic (MEG) studies further support the hypothesis ofthalamo-cortical dysrhythmia (TCD) in patients with complex regionalpain syndrome, whereas, interestingly, imaging studies show corticalthinning under chronic pain conditions. Similar physiological resultswere found using animal models of pain, thus allowing for more detailedmechanistic analysis, whereby a series of studies have validated thepathophysiology of thalamo-cortico-thalamic circuitry.

Rather than being the symptom of a disease process, chronic pain isitself a disease process. Chronic pain is unrelenting and notself-limiting and as stated earlier, can persist for years and evendecades after the initial injury. If not treated, chronic pain can leadto anxiety, fear, depression, sleeplessness and impairment of socialinteraction. Chronic, non-malignant pain is predominately neuropathic innature and involves damage either to the peripheral or central nervoussystems.

Nociceptive and neuropathic pain are caused by differentneurophysiological processes, and therefore respond to differenttreatment modalities. Nociceptive pain is mediated by receptors onA-delta and C-fibers which are located in skin, bone, connective tissue,muscle and viscera. These receptors serve a biologically useful role atlocalizing noxious chemical, thermal and mechanical stimuli. Nociceptivepain can be somatic or visceral in nature. Somatic pain tends to be welllocalized, constant pain that is described as sharp, aching, throbbing,or gnawing. Visceral pain, on the other hand, tends to be vague indistribution, paroxysmal in nature and is usually described as deep,aching, squeezing and colicky in nature. Examples of nociceptive paininclude: post-operative pain, pain associated with trauma, and thechronic pain of arthritis. Nociceptive pain often responds to opioidsand non-steroidal anti-inflammatories (NSAIDS). Neuropathic pain, incontrast to nociceptive pain, is described as “burning”, “electric”,“tingling”, and “shooting” in nature and can be unrelated to a stimulussuch as an injury. Examples of neuropathic pain include:monoradiculopathies, trigeminal neuralgia, postherpetic neuralgia,phantom limb pain, complex regional pain syndromes and the variousperipheral neuropathies. Neuropathic pain tends to be only partiallyresponsive to opioid therapy.

As is discussed above, chronic pain is a significant clinical problem.Most potent treatment is opiate derivatives; however, these drugs areassociated with serious side effects. Moreover, one type of chronicpain, neuropathic pain (due to direct damage to the nervous system(peripheral nerves, spinal cord or brain)) is usually resistant totreatment. During peripheral neuropathic pain, the degree of pain isoften unrelated to the degree of tissue damage at the site of nerveinjury. Clinical data indicate abnormal activity pattern in patientswith chronic pain, particularly in the sensory thalamus (ventroposteriorlateral; VPL), a major nuclear relay for sensory information.

Chronic abnormal sensations (sensory neuropathies) following peripheralnerve injury are caused by long-term changes in brain activity patterns.Sensory neuropathies and abnormal brain patterns are reversible withdirect intervention in the brain by deep brain stimulation (DBS).

The data described herein was generated using an art-recognizedpre-clinical rat model of peripheral neuropathy (chronic constrictioninjury, CCI). The brain area studied was in the sensory thalamus(ventroposterior lateral; VPL), a major nuclear relay for sensoryinformation. The VPL on one side of the brain receives sensory inputfrom the contralateral side of the body (neurons in the VPLcontralateral to CCI were studied). Neuronal activity from singleneurons in the VPL was recorded in live animals under deep anesthesia asextracellular action potentials. Neuronal patterns recorded were eitherevoked by stimuli on the corresponding receptive field in the body orspontaneous (no stimulation of the receptive field). Sensoryneuropathies were tested using standard behavioral measurement ofthermal sensitivity to a heat stimulus (latency of withdrawal tomoderately noxious heat) in awake, unrestrained, non-anesthetized rats.For reversal of abnormal activity patterns, DBS was delivered in the VPLunder deep anesthesia during recording. For reversal of thermalhypersensitivity, DBS was delivered in the VPL in awake, unrestrained,non-anesthetized rats.

In rats with neuropathic injury, abnormal neuronal activity was recordedin the VPL contralateral to CCI (similar results were confirmed inanother model of peripheral neuropathy by spinal nerve ligation; SNL).The neuropathy-induced abnormal activity in all rats includedhyperexcitability of evoked responses, emergence of high spontaneousfiring and aberrant evoked burst (in addition to occasional spontaneousrhythmic firing in some rats). Abnormal neuronal activity occurredexclusively in neurons with receptive fields in the leg (supplied by theinjured sciatic nerve). Neuronal activity recorded from the VPL withreceptive fields beyond the injured leg, and those from theventrolateral medial (VPM) nuclear group (which receives major inputfrom the face), were not different from those in naïve rats. Tissuecollected from neuropathic rats (postmortem) showed localneuroinflammation in the VPL contralateral to CCI. DBS reversed allabnormal patterns of neuronal activity in the VPL (except spontaneousdischarge, which remained high in neuropathic rats), with no sideeffects. DBS reversed thermal hyperalgesia in neuropathic rats, with noside effects.

Pain Signature

The neuronal activity patterns that make up the pain signature can bedivided into two major categories: spontaneous and evoked. Spontaneousactivity is further divided between baseline activity (on-goingspontaneous discharge in the absence of overt bodily stimuli) andafterdischarge (on-going spontaneous discharge immediately following thecessation of a noxious bodily stimulus). Evoked activity is furtherdivided between activity in response to noxious (e.g. painful highpressure or pinch) or non-noxious stimuli (e.g. gentle touch or brush).To make use of the ‘signal’ (i.e. for the sensory to detect itreliably), the signal could be either detected in an autonomous ‘rigid’manner (device with pre-programmed fixed set of parameters), anautonomous ‘flexible’ manner (device capable to ‘learning’, i.e. withcapacity to correct for errors to improve reliability of accuratedetection), or recognized by outside observer (experimenter, healthcarepractitioner or self in the form of Biofeedback).

One way of objectively or empirically quantifying the signature is bycomputing the rate of firing (i.e. number of action potentials in time)for individual neurons. The data show, for example, that the firing rateduring pinch under pain conditions is higher compared to normal. Onepoint to consider is that, for example, the firing rate during pressureunder pain conditions is lower compared to that during pinch undernormal conditions. Thus relying on firing rates exclusively todistinguish normal from pain states will not suffice to program anautomated detector, unless advance or real-time knowledge of thestimulation state is obtained. Though burst characteristics are based onparameters different than firing rate (e.g. number of bursts, meanspikes/burst), the same argument also applies (overlapping data betweenspontaneous and evoked activities).

In spite of these apparent limitations, one alternative is to consider areal-life example. Evoked noxious events are rare throughout anindividual's daily activities, including those with chronic pain. Suchevents are usually the result of infrequent injuries sustained fromfalling or projectiles. Therefore, the category of activity evoked bynoxious stimuli could be ignored (including noxious heat, andconsequently, including afterdischarge). A major category of activitythroughout daytime is predominately evoked by light touch, secondary togentle touch such as clothing, tapping, ‘feeling’, etc. A second majorcategory is spontaneous activity. Of note, pressure and pinch-evokedactivities under pain conditions are exceedingly higher than any othertype of activity under normal or pain condition, constituting a ‘safetymargin’ for programming. If noxious events do occur, they would beinterpreted as exceeding a set limit for ‘pain touch’ anyhow, and theperiod of afterdischarge would fall within the therapeutic time windowand would therefore be prevented. Furthermore, the difference betweenspontaneous and pressure or pinch-evoked activities is exceedingly high,therefore allowing for the setting of 2 distinct zones of activitiestermed ‘normal’ or ‘pain’, respectively.

Another option for the design of a closed-loop device to detect painsignature, based on firing rate, is to couple the device to a mechanicalsensing probe on the affected area of the body (superficially on theskin) capable of detecting mechanical energies such as touch, pressureand pinch stimuli, as well as thermal energies such as hot/coldsurfaces, and relay this information to the closed-loop device inparallel to the main neuronal detector of the brain signature. Such adesign would enable an automated response while lessening the need foran observer or feedback from the subject to classify the type ofneuronal activity (i.e. spontaneous or evoked).

Other types of neuronal activities are also envisioned for the detectionof the signature. These include neuronal activity recorded directly orindirectly at the level of Local Field Potential (LFP: i.e., samplingfrom a neuronal population) detecting shifts in power spectra usingFourier type analysis, absence or emergence of new spectral peaks),electroencephalogram (EEG), magnetoencephalogram (MEG), in addition toother types of imaging techniques and brain scans (for example MagneticResonance Imaging, MRI and fMRI and Positron Emission Tomography or PET,etc.)

Sensor Design

The sensor part of the closed-loop device for pain management, or anopen loop sensor device for pain diagnosis, depends on the capability ofthe sensor to record neuronal activity (from single neurons or apopulation of neurons, directly or indirectly using surrogatemeasurements such as blood flow or volume). Such pain signaturemanifests high temporal and special resolutions, as the said neuronalactivity is generated by a specific population of neurons in the brain(hence close proximity of the probe is needed for specific detection ofthe electric signal), and that the activity pattern or changes thereofoccurs mostly in the order of milliseconds or seconds. While currenttechnology allows such high temporal and special resolutions usingimplantable microelectrodes, the use of other ‘sensor’ technologies, inparticular non-invasive EEG functional imaging is useful.

More importantly, design strategy considers the possibility of not onlyrecording from a single area or structure in the brain, or looking atmultiple areas or structures in the brain individually, but alsostudying the interaction between these regions under normal andpathological or pain conditions, as it is known that networkconnectivity in the brain is altered in chronic pain patients.Dysfunctional network connectivity will manifest by combined temporaland spatial analysis of neuronal activity among more than one brain areaor structure at any of the recording or detection levels discussedabove.

Stimulation Design

A closed-loop device is programmed to detect the pain signature andoperate upon detection of such signals to send a command to an operatorthat would deliver therapy with the aims of reversing the signature. Forexample, this device would be turned ON in wakeful states and OFF duringsleep, depending on condition severity and need. Furthermore, the deviceis optionally set to deliver a therapeutic pulse periodically orintermittently (e.g., every 2 hrs).

Clinical Application

In addition to being used for analgesia (decreasing existent pain), thedevice is used for anesthesia during invasive or surgical procedures, inparticular if anesthetics or sedatives are contraindicated. Moreimportantly, the diagnostic aspects of the device are useful in caseswhere subjects or patients are non-cooperative, unable to respond,cognitively impaired, facing language barrier, or where simply verbalreporting is unreliable (e.g., in the pediatric population or with adultdrug-seekers).

Deep Brain Stimulation

Embodiments of the invention provide techniques for developing a safe,effective and long-term treatment strategy for persistent pain using,for example, deep brain stimulation (DBS) for the relief of chronicpain. The techniques can include measuring electrical activity in apatient's brain to determine if a certain pain signature exists. Thiscan involve the use of, for example, electrodes implanted into apatient's brain. The technique can also include providing therapeuticelectrical stimulation to, for example, the brain of the patient atpredefined times, frequencies, voltages, periodicities, and currents.The electrical stimulation can be provided in response to detecting thepresence of the predefined pain signature in the patient in aclosed-loop design, or can be provided on a periodic basis in a openloop system (e.g., every 1-2 hours). Other embodiments are within thescope of the invention.

One embodiment includes the use of a closed-loop design that can enableneurostimulation to be triggered upon detection of, for example,abnormal neuronal activity linked to (or immediately preceding) painepisodes, thus reversing aberrant neuronal activity and attenuating (oreven preventing) pain, without interfering with ‘normal’ brain activity.An additional benefit can also be the delivery of high frequency current(e.g., >150 Hz) that blocks (or ‘jams’) neuronal firing with no reportedside effects.

Anatomically, a major relay station to ascending sensory information ispreferably targeted in the thalamus, based on empirical evidence showinga characteristic burst firing pattern recorded from the thalamus ofawake patients with neuropathic pain, which closely resembles thatrecorded from the thalamus of animal models of neuropathic pain. To thisend, it has been 1) identified a thalamic neuronal activity patternassociated with neuropathic pain in anesthetized rats (‘painsignature’); 2) determined an optimal stimulation protocol that reversespain-related thalamic firing; 3) achieved reversal of pain-relatedbehavior by neurostimulation.

A series of stimulation protocols have been tested and several have beenidentified that best achieve reversal of pain-related neuronal activitywith the least amount of current delivered in duration and intensity.High frequency stimulation (e.g., >150 Hz) can ‘jam’ neuronal circuitry,resulting in ‘lesion’ effects that are reversible. The brain circuitrytargeted would preferably be the pain circuitry directly, mainly thesensory thalamus. The data show that a brief pulse train at highfrequency typically effectively attenuates neuronal hyperexcitability inthalamic neurons associated with chronic pain, and attenuates painbehavior.

A neuronal activity pattern has been characterized in thalamic neuronsthat is associated with chronic pain. The rationale for choosingthalamic neurons is at least partially based on tests showing thatthalamic sensory neurons typically undergo distinctive plasticitychanges under conditions of spinal cord injury-pain, and that reversalof these plastic changes by pharmacologic treatment is linked toreversal of pain behavior. In support of this, data suggest thatthalamic sensory neurons with receptive field in the dermatome of theinjured sciatic nerve (a model of neuropathic pain) undergo distinctchanges, including hyper-responsiveness to peripheral stimuli, increasedspontaneous firing and increased probability of afterdischarge. Inaddition, these experiments have been validated in awake un-anesthetizedrats, and tested the anti-nociceptive effects of neurostimulation onnociceptive behavior in a rat model of chronic pain.

During normal nociception (e.g., FIG. 1), information about stimuluslocation and intensity is encoded in precise patterns of actionpotential firing. Individual neurons produce, and dynamically switchbetween, a multitude of discrete firing modes such as single spikes,bursts (e.g., which can be configured in a variety of ways givendifferences in timing and patterning), spindle waves and spike motiftrains termed ‘epochs.’ Firing patterns are a product of (and influence)neurons in directly wired local circuits and in widely distributedcircuits. One such circuit element, the thalamus, serves as an importantsensory relay to higher cortical circuits.

An overall increase in thalamic gain is associated with an increasedtransfer ratio at the thalamocortical synapse that serves to morepotently activate cortical circuits involved in pain sensation. In otherbrain areas, for example in the visual system, the information contentof bursts is typically higher than single spikes. In the hippocampus,the probability of generating at least one postsynaptic spike is higherfor bursts than for single spikes. Thalamic nociceptive neurons undergospontaneous firing activity in normal human subjects and rats,conferring distinct neuronal rhythmicity (oscillations) at definedresonant frequencies. Temporal coincidence of such activity patternswith cortical activity mediates functional states that characterizesensory experiences. Several neurological conditions can upset thistemporal coincidence, and abnormal thalamic activity has been linked tochronic painful conditions. For example, spinal cord injury-induced painbehavior is associated with a higher prevalence of spontaneous burstfiring in the ventroposterior lateral (VPL) nucleus of the thalamus, inaddition to an increased number of neurons with oscillatory firingpattern; burst intervals are more regular, between-event intervals arelonger and burst events contain more spikes.

Rhythmic network oscillation in the thalamus is modifiable by thalamicevents and external synaptic input. En passant axons of thalamocortical,in addition to corticothalamic, relay neurons receive tuning from thesurrounding nucleus reticularis feedback circuit that could bereconfigured after injury to the nervous system. Unstable or aberrantlyprocessed nociceptive inputs lead to abnormal generation oramplification of nociceptive information. Therefore, neuromodulation byneurostimulation is an effective strategy to treat and/or manage chronicpain.

Thus, in view of the foregoing, a therapeutic system comprises thefollowing: 1) a detector linked to a stimulator in a closed-loop deviceto detect and reduce abnormal brain activity, thus attenuating pain inan automated way; 2) a biocompatible closed-loop neurostimulation devicespecific for chronic pain, 3) surgical brain implant and testing of thedevice, and 4) clinical application for chronic pain treatment.

Referring to FIG. 2A, a deep brain stimulation (DBS) system 5 for usewith a patient 10 is shown. Preferably, the DBS system 5 includes apattern recognition system 15, a processor 20, a signal generator 25, ananalog-to-digital converter 30, and a digital to analog converter 35.While the DBS system 5 is shown in FIG. 2A as including separatediscrete blocks (e.g., 15, 20, 25, 30, and 35), other configurations arepossible. For example, the functionality of one or more of the blocks15, 20, 25, 30, and 35 can be combined into a single device and/orroutine. Furthermore, while FIG. 2A includes a number of discrete blocks(e.g., 15, 20, 25, 30, and 35), certain blocks may be omitted in someconfigurations (e.g., pattern recognition system 15 andanalog-to-digital converter 30 can be omitted in non-closed loopsystems).

The analog-to-digital converter 30 is configured to receive signals fromthe brain of the patient 10 via an electrical lead 40 operably coupledto an electrode 41, and/or any other device that can measure neuronalactivity (e.g., functional scanners). The electrical lead 40 can beconfigured to be implanted intracranially in the brain of the patient10, although, the electrical lead 40 can be configured to measureelectrical activity of the patient 10 in other areas (e.g., the VPL,hippocampus, and/or brain stem). Preferably, the electrical lead 40 isconfigured to be attached and/or in close proximity to a wide dynamicrange (WDR) neuron in the brain of the patent 10, although other neuronscan be used. Preferably, the WDR neuron is chosen as a function orpsychological correlate of chronic pain being felt by the patient 10.For example, the WDR neuron chosen can correspond to the portion of thebody which the patient 10 feels chronic pain (e.g., a neuroncorresponding to the right leg of a patient suffering from chronic painin their right leg, technically defined as a “receptive field”). Theelectrical lead 40 is configured to detect electrical activity in thebrain of the patient 10, and to relay the sensed information to thesystem 5. Preferably, upon receiving sensed information from theelectrical lead 40, the analog-to-digital converter converts the signalinto a form desired by the pattern recognition system 15.

The pattern recognition system 15 is configured to monitor the signalprovided by the electrical lead 40 to determine the presence of specificneuronal activity associated with chronic pain (e.g., the painsignatures identified in the exemplary data described herein). Forexample, the pattern recognition system 15 can be configured to detectan increase in spontaneous background firing, an increase in rate offiring evoked by external stimulus (e.g., pressure or pinch), rhythmicafter-discharge signaling, rhythmic oscillation, abnormal bursting, etc.Preferably, electrical lead 40 is configured to detect neuronal activity(e.g., a pain signature) in the sensory thalamus (ventralposterolateral, VPL) of the brain of the patient 10. The patternrecognition system 15 can be configured to detect at least two differentmajor types of neuronal activity spontaneous and evoked. Spontaneousactivity is typically independent or temporally not associated with thepresentation of an overt stimulus or identifiable cause. Spontaneousactivity can best be described as an increase in the rate of spontaneousactivity in pain subjects compared to naïve/normal. Evoked activity istypically activity correlated with an overt stimulus or identifiablecause. Evoked activity can best be described as an increase in the rateof evoked activity in pain subjects in response to peripherally appliednoxious and non-noxious cutaneous stimuli compared to naïve/normal. Inaddition, abnormal bursting activity can occur during both spontaneousand evoked firing in pain compared to naïve/normal.

The pattern recognition system 15 is configured to communicate with theprocessor 20, and is configured to provide information to the processor20 in a predetermined format over a network connection (e.g., a bus ornetwork connection in embodiments where the pattern recognition system15 is separate from the processor 20). The pattern recognition system 15can be configured to perform various signal processing functions on thesignals sensed from the patient 10 (e.g., frequency analysis, Fouriertransform, inverse Fourier transform, filtering, de-noising, thresholdanalysis, analysis of interspike intervals, analysis of burst cycleperiods, analysis of spikes within bursts, etc.).

The processor 20 can be configured to examine information provided bythe pattern recognition system 15 to determine the appropriate response.For example, the processor 20 is configured to differentiate betweenvarious patterns that can be recognized by the pattern recognitionsystem 15 and to determine an appropriate response. The processor 20 candifferentiate between multiple recognized patterns, and determine anappropriate response strategy using, for example, a look-up table. Theappropriate response can be nothing at all, or, for example, can be tocause an electrical signal to be provided to the brain of the patient 10via an electrical lead 45 operably coupled to an electrode 46.

The processor 20 can be configured to reverse the pain signature in thebrain of the patient 10 using neurostimulation (or more accurately,neuromodulation). For example, neuromodulation can include theapplication of electricity of a predefined voltage, frequency, current,and duration to the brain of a patient 10. Preferably, theneuromodulation applied to the brain of the patient 10 is configured to“jam” the neuronal activity of the patient 10 (i.e., rather than furtherstimulating it). Preferably, this neuromodulation is achieved byproviding high frequency current (e.g., between 150-200 Hz, 1-3 volts,1-3 mA, and substantially of 0.25-0.75 ms rectangular pulses of 1 secondduration (assuming tissue impedance of 1000Ω). Preferably, by deliveringa low voltage, brief, and high frequency pulse to neuronal structuresthat preferentially respond to pain stimuli, the pain signature cantransiently be reversed back to “normal.” In addition, theneuromodulation protocol can be configured to transiently attenuate painbehavior in pain subjects to the level of that in naïve/normal, whileotherwise retaining tactile sensitivity. Electrical treatment isprovided to the deep brain, the VPL, and/or WDR neurons.

One exemplary treatment protocol includes electrical stimulation of thebrain of the patient 10 using periodic pulses of electricity. Forexample, intermittent pulses (e.g., 1 pulse, every 1-3 hours) can beprovided anywhere along the pain circuitry of the patient 10, butpreferably in the brain VPL nucleus. Preferably, each of the pulses hasa brief (e.g., 1 sec) duration, high frequency (e.g., 150-200 Hz), and alow voltage (e.g., 1.5-2 V). Preferably, each of these electrical pulsescan “jam” the overactive circuitry in the brain of the patient 10, basedon the temporal profile characterized herein. For example, for 2-3hours, pain symptoms can be temporarily relieved after providing anelectrical pulse.

The system 5 can be open-loop and/or closed-loop. In an open-loopembodiment, the system 5 can be programmed to provide electrical therapyaccording to a predetermined protocol (e.g., frequency, duration,voltage, amperage) without the use of the pattern recognition system 15and the analog-to-digital converter 30. In an open loop-embodiment, thetreatment protocol can be stored in a memory that is connected to theprocessor 20. In a closed-loop embodiment, the system 5 preferably usesinformation received via, for example, the pattern recognition system 15and the analog-to-digital converter 30 to treat cognitive, affective,and emotive neurological conditions, owing to the characterization ofthe pain signature described herein. While the closed-loop systemdescribed herein discusses the use of an electrical lead 40 implanted inthe brain of the patient 10, other configurations are possible (e.g.,receiving diagnostic information from fMRI, or PET scanning).Additionally, while separate leads (e.g., leads 40, 45 are discussed, asingle lead could instead be used for sensing and provision of theelectrical signals. Additionally, the system 5 can be controlledmanually (e.g., by actuating a button, or via a remote connection.

Electrophysiological Measurements for Pain Signature:

Electrophysiological measurements of wide dynamic range (WDR) thalamicneurons in chronic constriction injury (CCI) rats indicate elevatedevoked response to pressure and pinch stimuli in addition to rhythmicafter-discharge signaling and an increase in spontaneous backgroundfiring (FIGS. 3 and 4), in addition to abnormal burst. The group of ratsthat underwent CCI followed by thermal behavioral testing (n=10) displaya statistically significant (P<0.05) decrease of the ipsilateral hindpawwithdrawal reflex over the course of one week, with a marked separationin the withdrawal latency of the ipsilateral and contralateral hindpaws(FIG. 5). Treatment efficacy was assessed in part based on the reversalof this known effect.

Anesthesia:

No significant difference resulted in neuronal activity underintravenously administered pentobarbital sodium as compared withisoflurane gas anesthesia (FIG. 6). For this reason, animals were testedexclusively with isoflurane gas and generalizations may be appliedacross experiments with a variety of anesthetization methods.

Deep Brain Stimulation:

Deep Brain Stimulation of CCI animals resulted in an attenuation of meanfiring rate in response to all forms of mechanical stimuli, in additionto a statistically significant decrease in afterdischarge (FIGS. 7 and8). Furthermore, behavioral testing of awake DBS rats in group 6revealed a corresponding increase in withdrawal latency following highfrequency DBS (FIG. 9; data represent values normalized to pre-FHS orBaseline 100%).

Histology:

Postmortem histological analysis of these rats as compared with CCIcontrol animals is indicative of a statistically significant bilateralincrease in VPL Ox 42 antibody staining (P<0.05) while levels of GFAPantibody staining remain constant (FIGS. 10 and 11).

FIG. 12 shows characterization of bursts in response to various stimuli.The Requirements for defining bursts were:

Maximum interval signifying burst onset (6 ms)

Maximum interspike interval (9 ms)

Longest increase in interspike interval within a burst (2 ms)

Minimum number of spikes within a burst (2).

The following methods were used to generate the data described herein.

CCI: Chronic Constrictive Injury (CCI) was induced 7-9 days prior todata acquisition. Animals were anesthetized with isoflurane (2.5%). Thesurgical procedure consisted of a modification of the original looseligation model designed by Bennett and Xie. The process involvedisolation of the sciatic nerve via blunt dissection of the bicepsfemoris followed by a unilateral loose ligation with 5-0 gauge chromicgut ligature at three sites above the branching of the nerve, 1 mmapart. The ligation initiates an inflammatory response that results inchromic gut constriction of the nerve. Following the surgery, overlyingmuscles and skin were closed with 4-0 nylon sutures and the rodents wereallowed time for recovery. Thermal hyperalgesia resulting from CCI hasbeen found to remain relatively constant for a period of 5-27 daysfollowing the injury.

Electrophysiology: Single unit firing-unit recording (i.e. samplingneuronal activity one at a time) was recorded under deep anesthesia(1.5% Isoflurane). Extracellular single-unit recordings in and were madewith a 0.005″ 5M Ω Teflon-coated silver microelectrode (A-M Systems,Carlsborg, Wash.). DBS animals were implanted with a modified electrodeas shown below (FIGS. 14, 15, 16). Each subject was placed in astereotaxic frame, and a limited craniotomy exposed the brain surfacevertical to the recording sites within the VPL [Bregma (−3.3; −2.5);lateral (2.8; 3.6); vertical (5.4; 6.4)] (FIG. 16). Electrical signalswere amplified and filtered at 3000 Hz and processed with a CED micro1401 data acquisition system and SPIKE-2 software (Cambridge ElectronicDesign, Cambridge, England).

Waveforms were sorted to extract activity of a single neuron usingautomated template-matching. A hydraulic micropositioning device (KopfInstruments, Tajunga, Calif.) was employed in all vertical electrodepenetrations through nervous tissue. As the microelectrode is loweredinto the estimated region, a single “unit” or neuron can be isolated bystimulating the suspected somatosensory receptive field via tapping,brushing, pinching the skin, or manipulating the limbs of theanesthetized subject until excitation at the location of the electrodetip is measured via changes in current. This process was used in orderto identify VPL units innervated by the sciatic nerve. Spontaneousactivity was then measured, followed by evoked responses to mechanicalstimulation within the receptive field. Six mechanical stimuli wereapplied during each recording session: (i) brush (BR); (ii-iv)increasing intensity von Frey filaments (0.6 g, 8 g, and 15 g forces);(v) pressure (PR); (vi) pinch (PI). Wide Dynamic Range (WDR) thalamicneurons were specifically targeted based on their response to each ofthe mechanical stimuli.

Alternative Anesthesia Preparation: During preliminary trials, anadditional cohort of animals underwent either tracheal intubation forthe administration of 1.2%-2% isoflurane, or IV cannulation for theadministration of pentobarbital sodium (40 mg/kg/hr) prior toelectrophysiological recording. The purpose of these groups was toestablish the minimal effect of anesthesia type and level on VPL firingactivity.

DBS: After measurements of at least 2 consecutive series of recordingspontaneous and evoked activities, the electrode was disconnected fromthe recording equipment. The cathode of an isolated pulse stimulator wasconnected to the electrode and the anode was connected to the skin ofthe rat at the base of the head, acting as a body ground. Preliminaryrectangular pulses 0.5 ms in width were applied at a frequency of 100 Hzat 0.5V for 1 s. Immediately after stimulation, the electrode wasdisconnected from the stimulator and reconnected to the recordingequipment and recording resumed. Background activity was recorded for 40s and progressive mechanical stimuli as described above were thenapplied for a duration of 20 s each with 40 s rest in between each. Forany given unit, when there was no apparent change in activity,electrical stimulation was applied again with an increase in intensity(to 1.0 V or 1.5 V), frequency (from 100 Hz to 200 Hz), or number (5times every 3 s) of stimuli. The maximum stimulation was 1.5V at 200 Hzfor is repeated every 3 s for a total of 5 pulse events. When there wasan apparent inhibition of the responses to at least one mechanicalstimulus, DBS was stopped and consecutive electrophysiologicalrecordings of a series of spontaneous and evoked activities were testedevery 10 min.

Behavioral Testing: Behavioral tests of the CCI rats were performed withrespect to thermal and mechanical stimulation in order to verify thepresence of allodynia and hyperalgesia. Each animal was placed in aPlexiglas chamber situated on an elevated glass plate 30 minutes priorto testing for acclimatization. The thermal behavioral test consists offocusing a radiant heat source (4.7 amps) through the glass floor ontothe plantar surface of the rat's hind limb, resulting in withdrawalbehavior. The measured withdrawal latency is defined to begin at theonset of laser beam exposure and end upon movement of the rat hind pawfrom the floor surface. Five stimulation pulse events separated by 5 minwere averaged for each hindpaw and reported as the withdrawal latencyfor a given session. In order to test the effectiveness of HFS therapyon awake rodents, one group of animals underwent behavioral testingthroughout the DBS treatment regimen. DBS electrodes were held in placewith orthodontic resin and microelectrode leads were stored in a smallplastic container surgically implanted at the base of the skull duringbehavioral trials. All DBS behavioral testing animals received initialstimulation at 1.5V and 200 Hz within 6-8 days post surgery. Baselinepre-operative behavioral data was recorded for analysis beginning oneday prior to initial neurostimulation. Following the DBS event,behavioral tests were repeated 5 minutes and 30 minutes post treatment.

Histology and Image Analysis: In addition to verifying electrodeplacement, supplementary postmortem tissue analysis was used to identifythe activation levels of glial cells in the region of interest. Thisprovided the opportunity to assess microgliosis and astrogliosisassociated with glial scarring. In order to obtain images for subsequentanalysis, animals are anesthetized (5% isoflurane) and transcardiallyperfused with ice cold phosphate buffered saline (PBS) supplemented with10 USP units of anticoagulant Heparin Sulfate for 5 minutes (10 ml/min)followed by cooled 4% paraformaldehyde (PFA) in PBS for 5 minutes (10ml/min). This fixation process was used in order to preserve nervoustissue form degradation. Following decapitation with a small animalguillotine, the head was stored in PFA over night. The brains were thenremoved and stored in cold 30% sucrose until fully impregnated. Theformalin-fixed brains were blocked in the desired orientation and placedin tissue-embedding media (O.C.T. Compound 4583, Tissue-Tek). Brainswere stored at −80 degrees Fahrenheit and cut into 30 μm sections with amicrotome. These sections (ranging from Bregma −2.12 mm to −4.16 mm)were mounted on slides, dried, and stained with OX-42 or GFAP forfurther analysis of microglia or actrocytes, respectively. Allhistological images were captured via fluorescent microscope (Eclipse80i, Nikon with X-cite 120 EXFO fluorescent illumination). Photographswere taken via a high sensitivity digital camera (Retiga Exi Fast 1394,Q Imaging), and were then uploaded and digitally analyzed using IP LABsoftware (version 3.94r4, Scanalytics Inc). For quantitative comparison,the mean grayscale value of a 500×500 pixel region of interest for eachimage was used as an approximate measure of cell density.

The subject matter described herein can be implemented in digitalelectronic circuitry, or in computer software, firmware, or hardware,including the structural means disclosed in this specification andstructural equivalents thereof, or in combinations of them. The subjectmatter described herein can be implemented as one or more computerprogram products, such as one or more computer programs tangiblyembodied in an information carrier (e.g., in a machine-readable storagedevice), or embodied in a propagated signal, for execution by, or tocontrol the operation of, data processing apparatus (e.g., aprogrammable processor, a computer, or multiple computers). A computerprogram (also known as a program, software, software application, orcode) can be written in any form of programming language, includingcompiled or interpreted languages, and it can be deployed in any form,including as a stand-alone program or as a module, component,subroutine, or other unit suitable for use in a computing environment. Acomputer program does not necessarily correspond to a file. A programcan be stored in a portion of a file that holds other programs or data,in a single file dedicated to the program in question, or in multiplecoordinated files (e.g., files that store one or more modules,sub-programs, or portions of code). A computer program can be deployedto be executed on one computer or on multiple computers at one site ordistributed across multiple sites and interconnected by a communicationnetwork.

The processes and logic flows described in this specification, includingthe method steps of the subject matter described herein, can beperformed by one or more programmable processors executing one or morecomputer programs to perform functions of the subject matter describedherein by operating on input data and generating output. The processesand logic flows can also be performed by, and apparatus of the subjectmatter described herein can be implemented as, special purpose logiccircuitry, e.g., an FPGA (field programmable gate array) or an ASIC(application specific integrated circuit).

Processors suitable for the execution of a computer program include, byway of example, both general and special purpose microprocessors, andany one or more processor of any kind of digital computer. Generally, aprocessor will receive instructions and data from a read-only memory ora random access memory or both. The essential elements of a computer area processor for executing instructions and one or more memory devicesfor storing instructions and data. Generally, a computer will alsoinclude, or be operatively coupled to receive data from or transfer datato, or both, one or more mass storage devices for storing data, e.g.,magnetic, magneto optical disks, or optical disks. Information carrierssuitable for embodying computer program instructions and data includeall forms of non-volatile memory, including by way of examplesemiconductor memory devices, (e.g., EPROM, EEPROM, and flash memorydevices); magnetic disks, (e.g., internal hard disks or removabledisks); magneto optical disks; and optical disks (e.g., CD and DVDdisks). The processor and the memory can be supplemented by, orincorporated in, special purpose logic circuitry.

To provide for interaction with a user, the subject matter describedherein can be implemented on a computer having a display device, e.g., aCRT (cathode ray tube) or LCD (liquid crystal display) monitor, fordisplaying information to the user and a keyboard and a pointing device,(e.g., a mouse or a trackball), by which the user can provide input tothe computer. Other kinds of devices can be used to provide forinteraction with a user as well. For example, feedback provided to theuser can be any form of sensory feedback, (e.g., visual feedback,auditory feedback, or tactile feedback), and input from the user can bereceived in any form, including acoustic, speech, or tactile input.

The subject matter described herein can be implemented in a computingsystem that includes a back-end component (e.g., a data server), amiddleware component (e.g., an application server), or a front-endcomponent (e.g., a client computer having a graphical user interface ora web browser through which a user can interact with an implementationof the subject matter described herein), or any combination of suchback-end, middleware, and front-end components. The components of thesystem can be interconnected by any form or medium of digital datacommunication, e.g., a communication network. Examples of communicationnetworks include a local area network (“LAN”) and a wide area network(“WAN”), e.g., the Internet.

Example 1 Single-Unit Physiology in the Ventral Posterolateral Nucleusof the Thalamus in Neuropathic Rats

Neuropathic pain secondary to nerve injury is often chronic andaccompanied by dysesthesias. It is linked to long-term changes inneuronal physiology, known as neuroplasticity, which is well describedin peripheral nerves and the spinal cord but relatively less understoodin the brain. In spite of recent advances in pharmacotherapy,neuropathic pain remains poorly managed.

An early clinical account of aberrant thalamic physiology wasdocumented, which was later localized to the intralaminar, medial andventral thalamic nuclear groups of patients with neurogenic pain,central deafferentation pain, as well as peripheral neuropathic pain.Under these painful conditions, single unit activity is generallydescribed in terms of higher probability of spontaneous firing,increased rate of evoked firing, ectopic bursting, and dysrhythmicactivity.

Clinical evidence of aberrantly firing thalamic neurons in chronic painis corroborated by data from animal models. In rats with central painfollowing spinal cord injury, neurons in the ventral posterolateral(VPL) nucleus of the thalamus manifest higher probability of spontaneousfiring, afterdischarge, increased evoked responses and characteristicbursting patterns. In comparison, little is known about changes in tonicor burst firing of VPL neurons following peripheral neuropathic injurywithout central lesion.

Nociceptive neurons in the VPL receive ascending projections mainly fromspinothalamic tract neurons and project to several cortical areasincluding the primary somatosensory cortex. Within the VPL, a group ofneurons responds to a wide dynamic range (WDR) of mechanical stimuli,phenotypically homologous to WDR neurons at spinal cord level whose rolein central sensitization and chronic pain is well documented.

In addition to the correlation between pain and neuroplasticity, thetherapeutic effects of neuromodulation by deep brain stimulation (DBS)further suggests that brain plasticity is likely to have functionalsignificance. For example, DBS in the periaqueductal gray and motorcortex effectively relieves pain symptoms and decreases the requirementfor pain medication. More than 1000 clinical cases of DBS for chronicpain were preformed in the seventies and eighties. Although the Food andDrug Administration (FDA) rescinded its approval in the late eighties,there has been resurgence of interest in this medical procedure in thelast decade with an emphasis on patient selectivity and, moreimportantly, understanding basic mechanisms. Regarding DBS in the VPL,information related to the effects of microstimulation onneuroplasticity and sensory phenomena is limited, with clinical studiesreporting mixed results.

Although the mechanisms of DBS are not well understood, stimulationfrequency represents a key factor, with high frequency stimulation(HFS, >100 Hz) mimicking the functional effects of ablation, alsoreferred to as ‘jamming’ of local circuitry. HFS in the VPL reducesmechanical allodynia in rats with peripheral neuropathy.

HFS can be used to inhibit hyperactive VPL neurons, thus reversingneuroplasticity and, consequently, behavioral hypersensitivity. Thefiring of single units extracellularly from VPL neurons in naïve ratswas recorded. Firing from neuropathic rats after chronic constrictioninjury (CCI) of the sciatic nerve was also recorded. The data show thattonic and burst firing patterns in rats with CCI were significantlydifferent from those in naïve rats and were partially reversed aftermicrostimulation in the VPL at high (but not low) frequency, withsubsequent attenuation of hyperalgesia.

The following materials and methods were used to generate the datadescribed in this example.

Adult Male Sprague-Dawley rats (250-300 g) were used in this study.

Chronic constriction injury (CCI). As previously described (Owolabi S A,Saab C Y (2006) Fractalkine and minocycline alter neuronal activity inthe spinal cord dorsal horn. FEBS Lett 580:4306-4310; LeBlanc B W, IwataM, Mallon A P, Rupasinghe C N, Goebel D J, Marshall J, Spaller M R, SaabC Y (2010) A cyclic peptide targeted against PSD-95 blocks centralsensitization and attenuates thermal hyperalgesia. Neuroscience167:490-500; both of which are hereby incorporated by reference), amodified CCI from the originally described model (Bennett G J, Xie Y K(1988) A peripheral mononeuropathy in rat that produces disorders ofpain sensation like those seen in man. Pain 33:87-107; herebyincorporated by reference) was performed. The sciatic nerve was exposedafter skin incision at the mid-thigh level and blunt dissection of thebiceps femoris under deep anesthesia (isoflurane 3-4%). Three chromicgut (5-0) ligatures were tied loosely around the nerve 1 mm apart,proximal to its trifurcation. After CCI, the overlying muscles and skinwere closed in layers with 4-0 nylon sutures and the animal was allowedto recover. Rats were then maintained under the same pre-operativeconditions and fed ad libitum. At day 7 after CCI, neuropathicmanifestations are persistent for several weeks thereafter.

Single-unit extracellular recording. Animals from naïve and CCI groupsunderwent extracellular single unit recording from VPL neurons accordingto established methods (Hains B C, Saab C Y, Waxman S G (2006)Alterations in burst firing of thalamic VPL neurons and reversal byNa(v)1.3 antisense after spinal cord injury. J Neurophysiol95:3343-3352; hereby incorporated by reference). The activity of 1-2units/animal was recorded. Rats were initially anaesthetized withisoflurane (4% in induction chamber), and maintained by trachealintubation (1.5%; interestingly, no difference was noted in the firingrate under isoflurane or pentobarbital sodium (60 mg/kg) anesthesia).The head was fixed in a stereotaxic apparatus (Kopf Instruments,Tujunga, Calif., USA) and skin incision and a limited craniotomy exposedthe brain surface vertical to the recording sites within the thalamus.Neuronal units were isolated from the VPL nuclei of the thalamus[respective stereotaxic coordinates in mm: bregma (−3.3, −2.5); lateral(2.8, 3.6); vertical (5.4, 6.4)]. Extracellular single-unit recordingswere made with a 5 MΩ Teflon-coated tungsten microelectrode (A-MSystems, Carlsborg, Wash., USA). Electrical signals were amplified andfiltered at 300-3000 Hz (DAM80, World Precision Instruments, Sarasota,Fla., USA), processed by a data collection system (CED micro1401mkII;Cambridge Instruments, Cambridge, UK) to construct peristimulus timehistograms. The stored digital record of individual unit activity wasretrieved and analysed off-line with Spike2 software (CambridgeElectronic Design, CED, Cambridge, UK). Once a unit was identified by agentle probing of the body surface, its receptive field was mapped andstimulated by an experimenter.

For testing evoked activity, six routine natural mechanical stimuli wereapplied in the following order: brush, by a cotton applicator to theskin; three von Frey filaments (0.6, 8 and 15 g) with enough force tocause buckling of the filament at a regular frequency of 1 applicationper sec; pressure, by attaching a large arterial clip with a weak gripto a fold of skin (144 g/mm²) and pinch, by applying a small arterialclip with a strong grip to a fold of skin (583 g/mm²). Multireceptiveunits were identified by their responsiveness to brush, pressure andpinch, and with increasing responsiveness to incrementing strength vonFrey stimuli. Care was taken to ensure that each stimulus was applied tothe primary receptive field, and that isolated units displayed actionpotentials that remained stable for the duration of each experimentusing Spike2 template matching. Firing activity was computed as meanfrequency of spikes/20 s, and evoked responses and after discharges werecalculated by subtracting the pre-stimulus baseline activity to yield anet increase in discharge rate. Afterdischarge was defined as continuousdischarge after noxious pinch stimulus removal for 20 s. Cursors wereset at the beginning and the end of the stimulus, and all of the spikesoccurring between the cursors were summed. Cursors were also set at thebeginning of the trace and after 40 s (baseline or un-evoked firing),and the spikes occurring during this period were summed to provide ameasure of the background activity. The two sums were divided by therespective duration and the resulting averages (spikes/s) subtracted toyield the value attributed to the response (total number of spikes/s inexcess of the background activity during the stimulus). One to twoneurons with individually mapped receptive field were recorded from eachrat. Neuronal activity was analyzed off-line using Spike2.

In some rats, the spinal cord was also exposed by laminectomy atthoracic (T4-T6) level and topical 2% lidocaine was applied using acotton pledget to the dorsal and lateral surfaces of the spinal cord,followed 10 min later by complete cord transection using fine scissorwhile recording from the VPL neuron continued.

Estimated charge density. A theoretical limit of 30 μC/cm2 has beenproposed for the maximal allowable charge density above which tissuedamage occurs (Medtronic (1998) DBS TM technical manual. Minneapolis:Medtronic; Kuncel A M, Grill W M (2004) Selection of stimulus parametersfor deep brain stimulation. Clin Neurophysiol 115:2431-2441; ShimojimaY, Morita H, Nishikawa N, Kodaira M, Hashimoto T, Ikeda S (2010) Thesafety of transcranial magnetic stimulation with deep brain stimulationinstruments. Parkinsonism Relat Disord 16:127-131; each of which ishereby incorporated by reference), based on the following formula:

$\frac{{Voltage}\mspace{14mu}(V) \times {Pulse}\mspace{14mu}{width}\mspace{14mu}\left( {\mu\; s} \right)}{{Impedance}\mspace{14mu}(\Omega) \times {electrode}\mspace{14mu}{SA}\mspace{14mu}\left( {cm}^{2} \right)}$

Accordingly, given the following approximations of stimulationparameters at 1 V, 500 μs width, 1500Ω and 0.02 cm² electrode tipsurface area, the charge density within the vicinity of the silvermicroelectrode tip used in our behavioral experiments is roughly 16μC/cm², i.e. below maximal density (charge density for Tungstenmicroelectrodes used in the acute electrophysiology experiments is muchlower due to higher electrode impedance). In addition, modeling studiessuggest the possibility of ‘current steering’ using bipolar stimulatingelectrodes so that the shape of the area subjected to stimulation canmore closely overlap with a particular region of interest in the brain,therefore improving stimulation efficacy and minimizing side effects.Referring to modeling studies (e.g., Butson C R, Maks C B, McIntyre C C(2006) Sources and effects of electrode impedance during deep brainstimulation. Clin Neurophysiol 117:447-454; Butson C R, McIntyre C C(2006) Role of electrode design on the volume of tissue activated duringdeep brain stimulation. J Neural Eng 3:1-8; Butson C R, McIntyre C C(2008) Current steering to control the volume of tissue activated duringdeep brain stimulation. Brain Stimul 1:7-15), the stimulation parameterswith a monopolar electrode would theoretically result in a sphericalelectric field with a radius of approximately 2 mm, whereas consideringthe bipolar electrode design and their orientation in the brain, anoptimal overlap was predicted between the electric field potential andthe VPL nucleus according approximations illustrated in FIG. 17.

Burst analysis. Burst events were identified using Spike 2 Burst scriptusing the following criteria: 6 ms of the maximum interval between twoevents that signifies the start of a burst, 9 ms of the longest intervalbetween two events within a burst, and 2 of the minimum number of eventsin a burst. The following parameters were calculated during therecording periods of background activity, six natural mechanical stimulievoked discharges and after discharge: Number of burst events, meaninter burst time (ms), and % spikes in burst:

$\frac{{Mean}\mspace{14mu}{{spikes}/{burst}} \times {Number}\mspace{14mu}{of}\mspace{14mu}{bursts}}{{Total}\mspace{14mu}{spikes}} \times 100$

Micro-stimulation in the VPL. To test the effect of microstimulation onneuronal firing in anesthetized rats, the same recording electrode wasused for microstimulation within the VPL. After identifying single unitsand recording pre-stimulation (baseline) firing rates, the electrode wasdisconnected from the recording equipment and connected to a stimulator(A-M Systems Isolated Pulse Stimulator). Rectangular pulses 0.5 ms widthwere applied at a frequency of 100 Hz at 0.5 V for 1 s. Immediatelyafter stimulation, the electrode was disconnected from the stimulatorand reconnected to the recording equipment and data acquisition resumedwithin 2-3 min after baseline measurements. For any given unit, if nochange in firing was apparent after stimulation, electrical stimulationwas applied again with an increase in intensity (1.0 V and 1.5 V),frequency (100 Hz and 200 Hz), respectively, up to 5 microstimulationpulses every 3 s. When at least one evoked response was modulated bymicrostimulation, DBS was stopped and consecutive electrophysiologicalrecordings of firing rates were tested every 10 min. Therefore, for anygiven unit, “minimum” stimulation consisted of a single 0.5 V, is pulseat 100 Hz, and “maximum” stimulation consisted of 5×1.5 V, 1 srectangular pulse at 200 Hz.

To test the effect of microstimulation on behavior in non-anesthetizedrats, bipolar silver wires (˜1.5 KΩ) were chronically implanted on theday of CCI. Electrode segments were fused together with Epoxy resinforming cathode and anode. Teflon coating was removed exposing 0.5 mm oneach electrode tip, which were separated by 1 mm from tip-to-tipvertically. Initially, the longer tip was connected to the recordingequipment and local field potentials were recorded to localize the VPLarea with a receptive field in the contralateral hindpaw (seedescription below for additional details on the orientation of theelectrodes relative to the VPL for optimal steering of electric fieldand overlap with VPL nuclear structure). When a distinct increase inactivity was recorded in response to mechanical probing of the hindpaw,the wires were fixed to the skull permanently using a screw andorthodontic resin while microelectrode leads were encased in a smallplastic container fixed to the base of the skull. Withdrawal latencieswere measured 5 min before (baseline) and up to 2 hr aftermicrostimulation (3×1.5 V, 1 s rectangular pulse at 200 Hz; A-M SystemsIsolated Pulse Stimulator).

Behavioral analysis. Thermal sensitivity of the paw was assessed bymeasuring the latency of the withdrawal reflex in response to a radiantheat source. Animals were placed in Plexiglas boxes on an elevated glassplate under which a radiant heat source (4.7 amps) was applied to theplantar surface of the hindpaw. Paw withdrawal latencies (PWLs) of fivestimulations, separated by 5 min rest, were averaged for each paw. For‘baseline’ pre-operative values, data were averaged for both paws as nodifference was observed in PWLs between paws.

OX-42 and GFAP immunoreactivity. Rats were anesthetized withpentobarbital (60 mg/kg, i.p.) then perfused intracardially withice-cold PBS followed by buffered 4% paraformaldehyde. Brains werepost-fixed with buffered 4% paraformaldehyde overnight, equilibrated in30% sucrose, and frozen to −80° C. in OCT cryogenic compound (TissueTekSakura). Coronal sections (30 μm) were adhered to glass slides andblocked with goat serum. Sections were stained for OX-42 (Santa CruzBiotech, mouse IgG, 1:50), or GFAP (Chemicon International, mouse IgG,1:100) overnight at 4° C. Slides were washed with PBS and probed withgoat anti-mouse IgG (VectorLab 1:2000), visualized with a Nikon EclipseFluorescent microscope, and images were captured using a Qiacam CCDcamera. Mean fluorescent intensity was measured using ImageJ (NIHv1.43n) in 3 predetermined non-redundant (160 μm)2 boxes within the VPLbilateral to CCI per slide in each animal.

Statistical analysis. All statistical tests were performed at the alphalevel of significance of 0.05 using parametric tests. Data were testedfor significance using one-way ANOVA to determine degree of variabilitywithin a sample and whether there was a difference between groups amongthe obtained means. Tests of factors including pairwise comparisons werecarried out where appropriate, with either the paired Student's t-testfor before-after comparisons or the two sample Student's t-test tocompare two groups. Data management and statistical analyses wereperformed using Excel and presented as mean±standard deviation.

Extracellularly recorded action potentials were isolated from singleunits in the VPL nucleus of the thalamus under deep anesthesia usingtemplate matching techniques. All units discharged action potentials atrelatively constant voltage amplitudes and responded with increasedfiring rates to contralateral mechanical stimuli. In a representativeexample from a naïve rat, peristimulus time histogram shows increasedfiring rate when noxious and non-noxious stimuli are applied to thereceptive field in the contralateral hindpaw, noting a graded responseto increased strengths of von Frey filaments, compared to almost absentspontaneous firing (FIG. 18A, upper panel). Seven days after CCI, evokedresponses to pressure and pinch stimuli are increased, while spontaneousactivity and afterdischarge are elevated (FIG. 18A, lower panel).Compared to naïve rats, the mean firing rates of VPL neurons withreceptive fields in the contralateral hindpaw in rats with CCI increasedsignificantly in response to brush and pinch to 246% and 137%,respectively, with emergence of ectopic spontaneous activity andsignificant elevation of afterdischarge to 243% (FIG. 18B and Table 1(FIG. 29)). In contrast, the mean frequency of evoked responses to brushand von Frey filaments (0.6, 8 and 15 g) in rats with CCI were notsignificantly different from corresponding values in naïve rats. Thus,sciatic neuropathy is associated with plasticity of WDR neurons in theVPL with receptive fields in the contralateral injured hindpaw.Plasticity manifests as selective hyperexcitability in response tonon-noxious pressure and noxious pinch, in addition to an emergence ofun-evoked firing at a high rate. Of note, evoked responses to von Freyfilaments (0.6, 8 and 15 g), pressure and pinch of VPL neurons withsomatic receptive fields excluding the hindpaws in rats with CCI werenot significantly different from corresponding values in naïve rats,except for a significant increase in brush-evoked responses after CCI,whereas spontaneous activity and afterdischarge were less than 1 Hz inboth naïve and CCI rats (FIG. 25).

In addition, spontaneous rhythmic oscillation was observed in 33% of VPLneurons recorded from rats with CCI. In one representative example, thefiring rate during oscillatory epochs reached that of the pinch-evokedresponse. However, rhythmic oscillation and brush-evoked responses wereabolished by complete transection of the spinal cord at thoracic level,whereas spontaneous firing remained high (FIG. 19A). One example (FIG.19B) shows a peristimulus rate histogram of the same unit superimposedover a sinusoidal curve during the period of rhythmic oscillation(before transection) compared to nearly flat rate histogram aftertransection. Mean amplitude and frequency of sinusoidal curves were24.4±8.2 spikes/s (peak-to-peak) and 0.0095±0.00035 cycle/s,respectively (FIG. 19C). These data indicated that, in addition to thehigh spontaneous firing rate, sciatic neuropathy is correlated with arhythmically ectopic firing pattern in a group of VPL neurons dependanton on-going peripheral and/or ascending input below thoracic level.

To test whether microstimulation within the VPL modulates the firing ofsingle units, HFS was delivered through the recording electrode and therate of firing was measured before and after micro stimulation. In ratswith CCI, graded attenuation of evoked firing was achieved withincremental increase in voltage amplitude at 100 Hz and a prominenteffect was noted at 1.5 V, whereas spontaneous activity was not affected(FIG. 20A). Results with 100 Hz and 200 Hz were comparable and thereforepooled together collectively. All mean firing rates were significantlydecreased up to approximately −50% within 10-15 min after HFS for allfiring modes except spontaneous activity (FIG. 20C and Table 2). Bycomparison, LFS at 25 Hz had no significant effect on neuronal firing inrats with CCI at 1.5V, the same voltage amplitude which was otherwiseeffective with HFS (FIGS. 20B, D and Table 2). Results with 25 Hz and 40Hz were comparable and therefore pooled together. Interestingly, even‘moderate’ HFS (mFHS; 1×100 Hz, 0.5 V, 1 s) resulted in significantpercent decreases in the firing rates of pressure and pinch-evokedresponses and afterdischarge in rats with CCI. In naïve rats, HFS alsoattenuated all evoked responses except for von Frey 8 g filament (FIG.26 and Table 4). Therefore, micro stimulation within the VPL at high(>100 Hz), but not low (>40 Hz) frequency effectively reversesneuroplasticity induced by sciatic neuropathy by attenuating evokedfiring and afterdischarge.

Because tonic and burst firing contribute to signal processing, severalburst parameters were measured for single units in the VPL withcontralateral hindpaw receptive fields in naïve rats and in those withCCI. FIG. 21 shows examples of burst firing during brush-evokedresponses from a naïve rat and another rat seven days after CCI. Innaïve rats, spontaneous bursts events were almost absent, whereas thosein rats with CCI were increased in number (FIG. 22 and Table 3).Spontaneous bursts were detected in only 2 out of 14 units from naïverats (mean burst events 0.4±0.3). Therefore burst parameters duringspontaneous activity in naïve rats were not analyzed. In contrast, burstevents were increased significantly for all firing modes in rats withCCI compared to those in naïve rats, which were attenuated after HFSwith significant changes for pressure and pinch-evoked responses (FIG.22 and Table 3). Similar trends were observed between groups for percentspikes in burst values, whereas changes in the opposite directions werenoted for mean interburst time values (i.e. values decreased for allfiring modes in rats with CCI compared to those in naïve rats and wereincreased after HFS). In general, therefore, bursting patternsconsistently deviated from normal after sciatic neuropathy reachingsignificant levels. These changes were consistently reversed in thenormal direction after HFS, indicating that HFS reverses severalaberrant features of neuroplasticity including tonic and burst firingproperties.

Although spontaneous tonic and burst firing at the single unit level inrats with CCI was not affected by microstimulation, studies were carriedout to determine whether HFS modulates the local field potential withinthe VPL. Normalized power spectrum (computed by fast Fourrier Transferand plotted using Spike2) of local field potential recorded from the VPLof a rat with CCI shows a dominant peak in the low β frequency range(10-20 Hz) which does not vary significantly in amplitude or frequencybefore and after HFS (FIG. 23), suggesting HFS causes minimal or nomodulation of spontaneous neuronal activity in the VPL at a populationlevel.

Since HFS parameters comparable to those used in this study have beendemonstrated to attenuate CCI-induced allodynia (Kupers R C, Gybels J M(1993) Electrical stimulation of the ventroposterolateral thalamicnucleus (VPL) reduces mechanical allodynia in a rat model of neuropathicpain. Neurosci Lett 150:95-98, hereby incorporated by reference),experiments were carried out to determine whether HFS also modulatesthermal hyperalgesia in rats with CCI. Consistent with priorobservations using this procedure (Saab C Y, Hains B C (2009) Remoteneuroimmune signaling: a long-range mechanism of nociceptive networkplasticity. Trends Neurosci 32:110-117; Saab C Y, Shamaa F, El Sabban ME, Safieh-Garabedian B, Jabbur S J, Saade N E (2009) Transient increasein cytokines and nerve growth factor in the rat dorsal root gangliaafter nerve lesion and peripheral inflammation. J Neuroimmunol208:94-103; LeBlanc B W, Iwata M, Mallon A P, Rupasinghe C N, Goebel DJ, Marshall J, Spaller M R, Saab C Y (2010) A cyclic peptide targetedagainst PSD-95 blocks central sensitization and attenuates thermalhyperalgesia. Neuroscience 167:490-500; each of which is herebyincorporated by reference), PWL in the injured hindpaw was significantlydecreased to 6.8±1.1 s compared to 10.6±1.9 s in the non-injured hindpawseven days after CCI, and relative to 11.1±1.6 s for the mean latency ofboth hindpaws pre-operatively (FIG. 24A), indicating that sciaticneuropathy reliably resulted in thermal hyperalgesia. Using bipolarstimulating electrodes chronically implanted contralateral to sciaticinjury on the day of CCI, HFS voltage at 1.5 V was delivered within theVPL while testing the thermal withdrawal reflex. Under sham conditions(connecting the electrode to the stimulator without voltagestimulation), withdrawal latency in the injured hindpaw remaineddecreased compared to the non-injured hindpaw (FIG. 24B). However,withdrawal latency in the injured hindpaw was transiently reversed 5 minafter HFS with reproducible effects after 2 hr. The mean withdrawallatency was transiently and significantly reversed from 6.3±0.9 s to9.1±0.1 s and 7.3±0.1 s at 5 min and 10 min after HFS, respectively, inthe injured hindpaw. Of note, the withdrawal latency in the non-injuredhindpaw also increased after HFS, however, this change was notsignificant (FIG. 27).

Lastly, GFAP and OX-42 were quantified in tissue sections in or aroundthe tip of the chronically implanted electrodes in the VPL, whichrevealed no significant changes in expression compared to thecontralateral VPL (FIG. 28), indicating limited glial reactivity toelectrode implantation and HFS.

Peripheral neuropathic injury is associated with neuroplasticity of VPLneurons with receptive fields in the contralateral injured hindpaw.Abnormal physiologic properties include higher rate of spontaneousfiring, increased rates of afterdischarge and evoked firing in responseto non-noxious and noxious mechanical stimuli. In addition, significantchanges in burst firing and rhythmic oscillations were observed.Otherwise, the firing of neurons with receptive fields elsewhere in thebody was not changed, except for increased responses to brush stimuli.

The data confirmed enhanced spontaneous firing and increased activityevoked by brush, pressure and pinch stimuli in rats ten days after CCI.Noting minor modifications to the CCI model used in this study, theseobservations were exended to include hyper-responsiveness to von Freystimulation and afterdischarge at an earlier (day 7) time pointconcomitant with neuropathic behavior, in addition to other abnormalpatterns of tonic and burst firing.

Hyper-responsiveness, rhythmic oscillations and bursting in VPL neuronsare observed in a rat model of central neuropathic pain following spinalcord contusion. Relative to neuronal firing in normal rats, firing inrats with spinal lesion alternated between simple, burst and spindleepochs, whereas the number of spikes per burst decreased and interburstinterval was not changed. Compared to this study, different lesion sites(sciatic versus spinal) likely account for the incompletely matchingpatterns of aberrant firing in the VPL. However, spontaneous neuronaldischarge in rats with peripheral or central neuropathy remained highafter complete transection of the spinal cord, suggesting these changesin specific are likely ‘intrinsic’ to VPL neurons, while rhythmicoscillations described in this study depend on on-going ascending input.

In addition to firing rate, spike timing is a key factor in determininginformation content in spike trains. Burst spikes and isolated spikesboth contribute to the coding of stimulus-related information (MiddletonJ W, Yu N, Longtin A, Maler L (2011) Routing the flow of sensory signalsusing plastic responses to bursts and isolated spikes: experiment andtheory. J Neurosci 31:2461-2473; hereby incorporated by reference).Therefore, burst firing is an important feature of the neural code andcan effectively impact postsynaptic neurons, including upstream from theVPL in the somatosensory cortex. Bursting can be modulated by thetemporal frequency content of incoming signals, which in the case ofperipheral neuropathy is significantly altered at peripheral and spinalcord levels. The duration of bursts and the relative timing of burstspikes can encode specific stimulus features. Neurons in the lateralgeniculate nucleus discharge bursts and isolated spikes in response tovisual stimuli, with different stimulus conditions preferentiallyevoking different bursting patterns. Bursting has also been reported inthalamocortical projection cells, including the auditory and thesomatosensory systems. Although the functional significance of burstingin VPL neurons and modulation thereof under chronic pain conditions areunknown, interestingly, short-term plasticity of thalamocorticalsynapses is thought to accentuate the sensitivity of cortical responsesto ascending sensory input.

Burst firing has been documented in the ventral thalamus in a patientwith root injury and occurred during episodes of self-reportedtouch-evoked allodynia. Direct microstimulation within a thalamicnucleus that contains abnormally active neurons produces burningdysesthesia in patients with spinal deafferentation pain, as well aswith root injury pain, whereas microstimulation in the same area mightalso produce pain relief. These observations suggest that the aberrantphysiology of thalamic cells may be directly related to thedysesthesias, whereas the functional outcome depends on the paincondition and the neuro stimulation protocol. It's worth noting thatchanges in the patterns of burst firing, rather than burst firing prese, might be a reliable marker for pain-related plasticity. For example,burst firing can occur in deafferented subjects without pain.

HFS in CCI rats caused a ‘reversal’ effect on abnormal bursting patternsin the direction of normal condition, showing consistent results acrossall firing modalities. This is in agreement with the premise that HFS inthe therapeutic range for motor disorders works mainly by inhibitingneuronal firing or neuronal ‘jamming’. The data described herein relatesto hyperactive neurons in the VPL and a comparison of the effects of HFSand LFS on neuronal firing at the single unit level. Whereas HFSeffectively reversed neuronal hyper-responsiveness, spontaneous activitydid not change and overall responsiveness to mechanical stimuli wasdiminished but not abolished. Prior to the invention, no study comparedthe effects of varying stimulation frequency on analgesia. It isinteresting to note that low frequency (50 Hz) stimulation in the VPLproduces little or no analgesia in naïve rats. Data using in vivo andcomputational models suggest that high frequency signals suppressbursting by transiently interrupting the depolarizations caused bylow-frequency signals, for example those evoked by peripheral mechanicalstimuli. In a clinical setting, single units in the intralaminarthalamic nuclei of patients with chronic deafferentation pain dischargeaction potentials spontaneously at a high rate, often rhythmically. Inthese patients, bursts are described as short (2-6 spikes/burst) with afrequency of 1-4 burst/s, or long (30-80 spikes/burst) with a similarfrequency. As described herein, spontaneous burst firing matched wellpredominantly with the short bursting mode (2.4±0.1 spikes/s and 0.6±0.4burst/s; values derived from data in FIG. 22 and Table 4).

In rats with central pain, the firing of neurons in the somatosensorycortex is also changed in ways similar to those described for VPLneurons. Dysfunctional thalamocortical communication may underliecognitive disorders and sensory disturbances resembling tactileallodynia and thermal hyperalgesia, common symptoms of chronic pain.Analysis of magnetic encephalography activity in patients with complexregional pain syndrome shows a distinct shift in power spectra relativeto normal subjects, suggesting that the physiological changes in thebrain associated with chronic pain may manifest as significantdisturbances in network connectivity. Corroborating theseelectrophysiological data, imaging studies reported several brainregions with decreased grey matter, most commonly in the cingulate,orbitofrontal, and insular cortices. Some studies also show changes inprimary and secondary somatosensory cortices and the thalamus. Thissomewhat diffuse anatomical distribution reflects the co-morbidity ofchronic pain with several affective disorders, as well as cofoundingvariables caused by various medications in clinical studies involvingpain patients.

One important consideration is that of potential tissue damage as aresult of microstimulation. However, the use of an optimal chargedensity during microstimulation in behavioral experiments and absence ofglial activation indicate little if any tissue damage at the stimulationsite using the methods and systems described herein.

The data demonstrated anti-nociceptive effects of HFS on thermalhyperalgesia in rats with CCI, complementing previous data showingsimilar effects in the mechanical allodynia test in the same animalmodel, also using HFS of comparable stimulation parameters. It has beendemonstrated clinically that electrical stimulation of various sites ofthe brain, such as the periaqueductal gray matter (PAG), median thalamicnuclei, as well as less commonly targeted areas such as thepontomesencephalic parabrachial region, are effective in relievingchronic pain that is non-responsive to standard pharmacotherapy.

Neurons in the PAG, known to mediate descending anti-nociceptive controlunto lumbar dorsal horn neurons, could be activated by electricalstimulation in the VPL, an influence which is not affected by systemicadministration of naloxone, suggesting that the VPL-PAG analgesicpathway is unlikely to involve the opioid system. This mechanismprovides an alternative explanation to the widely held idea that theanalgesic effects of subcortical brain stimulation is the result ofactivation of a descending ‘pain suppressive system’ concentrated in theperiventricular and periaqueductal regions, which blocks nociceptivetransmission at the level of the spinal cord. Primate spinothalamictract (STT) neurons in the spinal cord are inhibited bilaterally by lowcurrent (<25 μA) high frequency (333 Hz) stimulation in the VPLunilaterally, in support of data described herein showing increasedwithdrawal thresholds in both hindpaws in response to unilateralmicrostimulation in the VPL. In addition, VPL stimulation may causesufficient input to the somatosensory cortex to activate corticofugalinhibitory pathways, following thalamocortical-corticofugal projectionsinhibiting spinal cord nociceptive neurons. It is also possible that VPLstimulation activates antidromically axon collaterals of STT neuronsprojecting to the medial brain stem, including the PAG and nucleus RapheMagnus, thus resulting in analgesic effects.

Low-voltage stimulation in the VPL at high frequency can locally inhibitVPL neurons and subsequently the transmission of nociceptive signals tocortical areas. The mechanisms include one or a combination of causessuch as ‘jamming’ of a local nociceptive circuitry, activation ofinhibitory structures within a wider network, blockade of membrane ionchannels such as voltage-gated currents, depolarization blockade,synaptic exhaustion, and induction of early genes.

Example 2 Objective Diagnostic Index for Pain

Neuropathic pain is a neurological disorder that, prior to theinvention, lacked a reliable diagnostic. The methods and systems of theinvention provide a solution to a long-standing problem in painmanagement. An objective measure for pain leads to more accuratediagnosis, monitoring and optimizing therapeutics, thus amelioratingoverall clinical outcome. In addition, a physiological correlate of painis useful in the design of closed-loop neuromodulation systems.

Local field potential (LFP) and multiunit activity are extracellularlyrecorded signals from a local network of neurons. LFP represents thelow-frequency (<0.5 kHz) content of the raw recording generated bymembrane currents of the neurons in a local neighborhood of therecording electrode, whereas the high frequency (>1 kHz) contentrepresents neuronal action potential spiking. As such, the coordinatedactivity of cell populations is reflected by regular oscillations inLFPs, which has been proposed as a mechanism to optimize the recordingand analysis of network functions.

LFP is a good candidate for ‘pain signature’. Initially studied in greatdetail owing to their ease of recording with non-invasivemacroelectrodes, field potentials contain informative signals measuredout of the pool of a large number of spiking neurons while relating tosensory and motor phenomena. Changes in field potentials are triggeredby external events (evoked potentials) when induced by a stimulus (e.g.noxious mechanical stimulus or non-noxious tactile stimulus) or byinternal cortical dynamics (intrinsic oscillations or rhythms) due tothought processes (e.g. spontaneous pain). Therefore, analysis of LFPsallows for the study of multiple neuronal networks simultaneously, forexample thalamo-cortical networks thought to underlie normal states ofconsciousness and arousal, as well as neurological disorders such aspain and depression. Field potentials are recorded intracortically (LFP,using penetrating electrodes), supracortically (EcoG electrodes), on thescalp (EEG), or even with magnetoencephalograhy (MEG) which measurestangential fields.

The amount of information contained within a brain signal diminishes asit passes from intra- to extra-cellular, from single to multiunit tofield potentials, and from LFP to ECoG to EEG to MEG. Many have recentlyargued in favor of balancing optimal information content with lessinvasive recording for translational purposes.

Data showing pain-related brain activity is described below (FIGS. 30,31, 32. Characteristic burst firing is recorded from the thalamus ofpatients with neuropathic pain (FIG. 30). This bursting pattern closelyresembles that recorded from the thalamus of an animal model ofneuropathic deafferentation pain (FIG. 31), whereby reversal of thisneuronal activity was associated with attenuation of pain behavior.

Additional patterns of brain activity in the VPL nucleus of the thalamusrelated to pain were identified in a rat model of sciatic neuropathy.Recording single-unit action potentials, increased evoked firing weredemonstrated in response to tactile noxious and non-noxious stimuli,increased after-discharge following noxious stimulation, emergence ofspontaneous firing, as well as characteristic burst events. Furthermore,deep brain stimulation effectively reversed ‘pain signature’ andattenuated pain behavior.

A series of psychiatric disorders, including Tourette and pain, may beassociated with thalamocortical dysrhythmia (TCD). Synchrony of thalamicand cortical networks under normal conditions are thought to underlieconsciousness, whereby state-dependant (sensory or cognitive state)rhythms of thalamocortical relay neurons are continuously driven bycorticothalamic input resulting in oscillation, thus binding sensory orcognitive events in a unified percept. Some neurological disorders,however, can lead to disregulation of calcium channels in the brain,thus causing abnormal calcium spiking and high frequency burst inthalamic reticular nuclei, paradoxically driving the thalamocorticalnetwork into lower frequency oscillation (4-10 Hz) (FIG. 32). The factthat pain-related changes occur at single unit and MEG levels indicatesthat LFP (which is intermediate in terms of information content) can betranslated into less invasive EEG. Whether it can also be translatedinto MEG depends to some extent on the results of this study.

Neurons at multiple stages of the somatosensory pathway displayoscillations at 7-12 Hz, including in somatosensory cortex (S1) and theventral posterior nucleus of the thalamus. Therefore, pain is associatedwith a characteristic pattern of brain activity embodied in LFPs, whichis useful for objective diagnosis and as well input signal in aclosed-loop technology for pain therapy. Pain-related LFP can bereversed by spinal cord stimulation (SCS) or peripheral nervestimulation (PNS), thus closing the loop of a hypothetical automatedsystem.

Example 3 Local Field Potential (LFP) Measurements

Methods for single unit recording are described above, and additionalstudies are described below.

Adult male Sprague Dawley rats (200-250 g) were used. Data werecollected and analyzed by observers blinded to the animal's treatmentwhenever possible.

The pain model utilized chronic constriction injury of the sciaticnerve. This is a widely used model of mononeuropathy that yieldsreliable pain behavior in rats. Rats are deeply anesthetized withisoflurane (1.5-2%) and the sciatic nerve is loosely ligated with 4chromic gut (4-0) sutures. After CCI, the overlying muscles and skin areclosed in layers with 4-0 nylon sutures.

Pain behavioral is tested daily to determine mechanical and thermalsensory thresholds. Pre-operative testing generally begins 2 days priorto CCI and once per day for 10 days after CCI. Mechanical sensorythresholds are determined by the standard Dixon up-down method utilizinga series of von Frey filaments applied to the glaborous surface of thepaw. Thermal hyperalgesia is measured by latency of paw withdrawal inresponse to a radiant heat source. Rats are placed in Plexiglas boxes onan elevated glass plate under which a radiant heat source (4.7 amps) isapplied to the plantar surface of the paw and rats are free to escapefrom applied stimuli. The temperature that the paw can be subjected tocan reach a maximum of 57° C. for a transient time of less than 3 sec.Rats that don't display significant pain behavior are excluded from thestudy.

Electrophysiology evaluations are carried out as follows. Afterconfirming pain behavior, a minimal craniotomy at day 7 after CCI/shamunder deep anesthesia (3% isoflurane) exposes the cortical surfacevertically above the VPL or somatosensory cortex (SI) identifiedaccording to a rat brain atlas. LFP recordings (CED 1401) are made usinga tungsten microelectrode (125 μm, 12 MΩ) by low-pass filtering of theextracellular field potential below 300 Hz. Microelectrodes arepositioned stereotaxically in areas of the VPL or SI with identifiablereceptive fields in the injured dermatome (hindpaw on the side of CCI).Bands mostly in the low frequency ranges (within the ranges of θ, α, andβ rhythms), as well as higher ranges (100-500 Hz), were studied for‘shifting’, spindle wave occurrences and epochs will also be identified.Off-line analysis of spectral power was conducted using Spike 2 software(CED 1401). Evoked responses (triggered by tactile noxious andnon-noxious stimuli) and spontaneous activity was recorded. LFP wasrecorded contralateral to CCI, as well as ipsilateral to CCI in the sameanimals (‘internal’ control group), in addition to naïve animals (FIG.35). Since recording from multiple brain structures will subject ananimal to multiple electrode penetrations, separate groups were used forLFP recordings in VPL versus SI.

Statistical analysis was performed using SigmaStat software. Analysis ofvariance (ANOVA) and parametric tests were used for normally distributeddata with p<0.05 considered significant. Otherwise, non-parametric testswere used. Paired t-tests will look at the effect of a manipulation(e.g. evoked responses or the effect of SCS) within the same group ofanimals (before/after).

Adult male Sprague Dawley rats (220 g) were used to induce chronic painby chronic constriction injury of the sciatic nerve (CCI). Pain behaviorwas tested on day 7 post-operatively before brain recording and thermalhyperalgesia was confirmed, showing significant decrease of withdrawallatency in the injured paw compared to the contralateral un-injured paw,a reflex triggered by a controlled radiant heat source.

After confirming neuropathic pain behavior, LFP recordings were madeunder deep barbiturate anesthesia from the ventral posterolateral (VPL)nucleus of the thalamus bilaterally, with the side ipsilateral to injuryserving as control (receiving ascending information predominantly fromthe un-injured paw). The location of the microelectrode was confirmed bystereotaxic coordinates (according to a rat brain Atlas) and byincreased in background firing in response to gentle brushing of thecorresponding receptive field in the contralateral paw (FIG. 33).

After confirming electrode location in the VPL, spontaneous activity, aswell as activity in response to brushing of the contralateral paw, wasrecorded for 20 s each. Off-line analysis revealed distinct peaks ofincreased spectral power under different conditions and majordifferences were found between control (normal side) and CCI (injuredside) (FIG. 34).

A reported leftward shift in MEG power spectrum of spontaneous activityin patients with chronic pain compared to control is in agreement withFIG. 34 (left panels). Thalamic LFP recordings from patients withTourette Syndrome, a cognitive/movement disorder, emphasized asignificant correlation between the main LFP frequency and the frequencyof single-unit interbursts. Data described herein shows that the meaninterburst period of single-unit brush-evoked activity recorded from theVPL is approximately 400 ms for animals with CCI and 100 ms for naïve,thus predicting a rightward shift in power spectra from 2.5 to 10 Hzafter CCI, exactly matching with what we show in FIG. 34 (right panels).Therefore, the abnormal bursts described at single-unit level arecontributing to the shift in power spectra observed at LFP level.Prominent LFP power spectra was also described in the low frequency (2-7Hz), as well as in the α-band (8-13 Hz) but virtually absent β activity,also in agreement with FIG. 34 (right panels). A resemblance in brainLFP and EEG activities in the α-rhythms between awake humans and animalsunder barbiturate anesthesia has been observed, further validating theapproach and animal models used in these studies.

The patent and scientific literature referred to herein establishes theknowledge that is available to those with skill in the art. All UnitedStates patents and published or unpublished United States patentapplications cited herein are incorporated by reference. All publishedforeign patents and patent applications cited herein are herebyincorporated by reference. All other published references, documents,manuscripts and scientific literature cited herein are herebyincorporated by reference.

Further, while the description above refers to the invention, thedescription may include more than one invention. While this inventionhas been particularly shown and described with references to preferredembodiments thereof, it will be understood by those skilled in the artthat various changes in form and details may be made therein withoutdeparting from the scope of the invention encompassed by the appendedclaims.

What is claimed is:
 1. A system configured to treat peripheral pain, thesystem comprising: a processor configured to be coupled to an electricallead operably coupled to an electrode configured to sense electricalactivity in a patient, the processor configured to: detect a painsignature associated with peripheral nerve damage in the sensedelectrical activity; determine a treatment protocol in response to thedetected pain signature; and cause the treatment protocol to bedelivered to a sensory thalamus contained within the patient via theelectrical lead and electrode implantable within the sensory thalamus,the treatment protocol including providing at least one electricalsignal to the patient, the electrical signal comprising one or moreelectrical pulses being at least about 150 Hz, between about 1 and about3 volts, between about 1 and about 3 milliampere, and between about 0.25and about 1 second in duration.
 2. A system configured to treatperipheral pain, the system comprising: a processor configured toprovide an electrical treatment protocol to a sensory thalamus containedwithin a patient, the electrical treatment protocol being configured totreat chronic pain in the patient, the treatment protocol includingproviding at least one electrical signal to the patient using anelectrical lead operably coupled to an electrode implantable within thesensory thalamus, the electrical signal comprising one or moreelectrical pulses being at least about 150 Hz, between about 1 and about3 volts, between about 1 and about 3 milliampere, and between about 0.25and about 1 second in duration.
 3. A method of identifying a subjecthaving chronic pain of peripheral origin and related to peripheral nervedamage, the method comprising detecting, using an electrical leadoperably coupled to an electrode implantable within a sensory thalamusand using a pattern recognition processor, a pain signature associatedwith the peripheral nerve damage and comprising a pattern of neuronalfiring, said pattern comprising an elevated evoked response to stimuli,rhythmic after-discharge signaling, and increased spontaneous backgroundfiring.
 4. A method of preventing or reducing pain perception,comprising identifying a subject according to claim 3, and administeringto said subject at least one electrical signal to a sensory thalamuscontained within the subject, the electrical signal comprising one ormore electrical pulses being at least about 150 Hz, between about 1 andabout 3 volts, between about 1 and about 3 milliampere, and betweenabout 0.25 and about 1 second in duration.
 5. The method of claim 3,wherein chronic pain further comprises one or more of:monoradiculopathies, trigeminal neuralgia, postherpetic neuralgia,phantom limb pain, complex regional pain syndromes, sciatica, and aperipheral neuropathy.
 6. The method of claim 3, wherein the peripheralnerve damage comprises inflammation of a nerve.
 7. A method ofidentifying a subject having chronic pain of peripheral origin andrelated to peripheral nerve damage, the method comprising detecting,using an electrical lead operably coupled to an electrode implantablewithin a sensory thalamus and using a pattern recognition processor, apain signature associated with the peripheral nerve damage comprising apattern of burst-firing, each burst of said burst firing comprising atleast 10 times the number of spikes compared to a control non-painpattern, said burst firing comprising: (a) a maximum interval signifyingburst onset (6 ms); (b) a maximum interspike interval (9 ms); (c)longest increase in interspike interval within a burst (2 ms); or (d) aminimum number of spikes within a burst (2).